Our previous study successfully identified the relationship between activity in the hippocampus and the medial prefrontal cortex during active choice behavior in a spatial working memory task in which prefrontal neurons became phase-locked to the hippocampal theta rhythm and tightly correlated with hippocampal place cells prior to accurate choice responses. Our studies also identified a novel form of hippocampal activity during quiet wakefulness in which sequential place cell activity reflecting past behavior was reactivated during stopping at goal locations. Preliminary results have provided further evidence of reactivation of forward sequences reflecting future trajectories during stopping at non-goal locations. Together these findings suggest that interactions between the hippocampus and prefrontal cortex during both active behavior and periods of awake inactivity may contribute to learning of behavioral contingencies in choice tasks through both prospective evaluation of future states, and retrospective evaluation of past states, and that these interactions may serve as a general biological substrate for unsupervised reinforcement learning. The possible contribution of these events to reinforcement learning would further suggest the involvement of reinforcement related activity in areas known to express correlates of reward and expectation of reward such as the ventral tegmental area (VTA). The present proposal seeks to further elaborate the relationship between the structure of neuronal activity, and behavioral events involved in learning of simple reinforced spatial working memory tasks by conducting simultaneous multielectrode recording of neuronal ensembles at multiple sites within the medial prefrontal cortex area (RFC), the ventral tegmental area (VTA), and the CA1 region of the hippocampus during active behavior, awake inactivity, and during sleep. These aims will extend the basic relationship between behavioral correlates of PFC activity established in previous work to the newly discovered phenomena of forward and reverse hippocampal sequence memory reactivation during quiet wakefulness, and will identify novel correlates of reinforcement-related activity in the VTA and their relationship to activity in both the hippocampus and PFC as they may relate to the general process of reinforcement learning. Given the known involvement of these brain areas in a broad spectrum of cognitive functions and behavioral and neuropsychiatric disorders, including spatial navigation, memory encoding and retrieval, addiction, schizophrenia, autism, and attention deficit disorders, this study will provide important insights into basic mechanisms that may contribute to learning, memory, and cognition, and establish novel biological substrates for computational models of neural function. [unreadable] [unreadable] [unreadable]